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Background

While recent advances in pediatric oncology have improved outcomes with more than 80% of children surviving, there is an increased cumulative incidence of treatment-related chronic health conditions and late effects of therapy that have become widely recognized.

The Childhood Cancer Survivor Study (CCSS) was established to monitor these late effects. This is a retrospective cohort study which examines patients who have survived at least 5 years after diagnosis of childhood cancer. Patients with childhood cancers before the age of 21 during 1970-1986 were enrolled from 26 institutions across the US and Canada, and data is maintained and accumulated via review of medical records as well as healthcare provider and survivor survey-based reporting. The database is publicly accessible for research purposes.

In prior analysis of the CCSS data, the cohort of survivors was found to have increased relative risk of chronic health conditions, including cardiovascular diseases, compared to their siblings. In fact, adult survivors had 5.9 times the risk of developing congestive heart failure, 5 times higher risk of myocardial infarction, and 6.3 times higher risk of valvular disease compared to their siblings.

The incidence, severity, and spectrum of chronic health conditions in this population during the fourth and fifth decades of life have not been well studied. Therefore, the purpose of this study was to define incidence and magnitude of risk for chronic health conditions compared to siblings among aging survivors.

Materials and Methods

The retrospective CCSS cohort was used for this study.

The analysis included 14,358 patients who had survived > 5 years after treatment for childhood cancer. Of the total number of cases, 13,268 were evaluable.

The control group consisted of a sibling cohort (n = 4,031).

Self-reported health conditions were classified using NCI CTCAE 4.0 grading system. Conditions that developed during the first 5 years following treatment were excluded.

Cumulative incidence of a new chronic health condition was calculated from age 26 years.

Results

Median age at last follow-up for survivors was 31 yrs, range 5-58. 39% of survivors were more than 35 years old. The sibling cohort was slightly older with a median age of 34 years old.

46% of survivors were female vs 52% of siblings.

Across all grades of disease (grade 1-5), 58% of survivors and 57% of siblings reported at least a single chronic health condition. Survivors appeared to develop the conditions earlier, with 60% of 20 year old survivors reporting a health condition while only 30% of siblings reported a chronic health condition at age 20.

However, between the ages of 50 and 60 years, siblings and survivors report similar rates of all grades of chronic health conditions.

Focusing on severe conditions, 24% of survivors reported grade 3-5 conditions while only 10% of siblings reported the same.

By age 20, 20% of survivors reported grade 3-5 toxicity while <5% of siblings reported conditions at age 20. At age 50, ½ of survivors noted grade 3-5 conditions vs 20% of sibling. In other words, a 20 year old survivor has the same number grade 3-5 conditions as a 50 year old sibling.

By age 50, 10% of survivors reported developing 3 or more grade 3-5 conditions. For siblings, <1% reported multiple grade 3-5 conditions at age 50.

When evaluating conditions at various time points, young adult survivors (<20 years old) demonstrated a 7 fold increased risk of severe chronic health conditions. However, this decreased to 4 fold compared to siblings between the ages of 20-35 and 5 fold over 35 years old.

The types of chronic health condition reported were most commonly new malignancy and cardiac conditions, with 15-20% of patients developing these conditions by age 50. For hearing and vision changes, the increases were modest with 3-5%. Surprisingly, there were very low rates of renal or respiratory grade 3-5 conditions.

Treatment effects appeared to drive development of conditions, as the authors demonstrated that for survivors who had not received chemotherapy or radiation, the hazard ratio, or increased risk, of conditions was only 1.9 compared to 4-fold for those who had received any chemotherapy or any radiation.

Author's Conclusions

As adult survivors of childhood cancer age, they continue to develop new and serious health conditions at substantially higher rates than their siblings.

20 year old survivors develop the same number of grade 3-5 conditions as 50 year old sibling counterparts.

The most common severe chronic health conditions developed by survivors included cardiac disease and second malignancies, with a more than 5-fold increase in the risk of developing these conditions.

These data emphasize the importance of placing a greater focus on investigations of premature aging and organ senescence in this high-risk population.

Clinical Implications

The study continues to shed light into the significant problems of treatment-related chronic health conditions faced by survivors of childhood cancers. It highlights the idea of premature aging, demonstrating that survivors develop severe conditions much earlier in life than their siblings. The data presented here also reiterates the critical nature of survivorship care plans and continued oncologic follow up for cancer survivors.

However, due to the retrospective nature of data collection and the self-reported outcomes, the results are intended to generate hypothesis and establish causality.

The limitations of this study include its retrospective nature. Additionally, all conditions are self-reported and rely on patients to know the severity of their illnesses.

While the CCSS is a wonderful tool with excellent follow-up, patients followed on this study were treated in the early 1970s to mid 1980s, using outdated radiation techniques and chemotherapy regimens no longer in use. Data regarding chronic health conditions for patients treated in the modern era will be of great interest when available.

Understanding the increased risk associated with prior cancer treatment will continue to aid healthcare teams in providing comprehensive survivorship care and surveillance. Interventions aimed at prevention and screening are necessary to mitigate the development of severe health conditions w hen possible.